Quinolinone derivatives and their pharmaceutical compositions

ABSTRACT

Compounds of formula I 
     
       
         
         
             
             
         
       
     
     in salt or solvate form, wherein W, R x , R y , R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  and A have the meanings as indicated in the specification, are useful for treating diseases mediated by the β 2 -adrenoreceptor. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.

This invention relates to novel salts, a process for their preparationand their use in pharmaceutical compositions.

In a first aspect, the present invention provides a compound of formulaI

in salt or solvate form,

where W is a group of formula

R^(x) and R^(y) are both —CH₂— or —(CH₂)₂—;

R¹ is hydrogen, hydroxy, or C₁-C₁₀-alkoxy;

R² and R³ are each independently hydrogen or C₁-C₁₀-alkyl;

R⁴, R⁵, R⁶ and R⁷ are each independently hydrogen, halogen, cyano,hydroxy, C₁-C₁₀-alkoxy,

C₆-C₁₀-aryl, C₁-C₁₀-alkyl, C₁-C₁₀-alkyl substituted by one or morehalogen atoms or one or more hydroxy or C₁-C₁₀-alkoxy groups,C₁-C₁₀-alkyl interrupted by one or more hetero atoms,

C₂-C₁₀-alkenyl, trialkylsilyl, carboxy, C₁-C₁₀-alkoxycarbonyl, or—CONR¹¹R¹² where R¹¹ and R¹² are each independently hydrogen orC₁-C₁₀-alkyl,

or R⁴ and R⁵, R⁵ and R⁶, or R⁶ and R⁷ together with the carbon atoms towhich they are attached denote a 5-, 6- or 7-membered carbocyclic ringor a 4- to 10-membered heterocyclic ring;

R⁸, R⁹ and R¹⁰ are each independently hydrogen or C₁-C₄-alkyl; and

A is selected from the group consisting of hydrogen succinate, fumarate,hippurate, mesylate, hydrogen sulphate, hydrogen tartrate, hydrogenchloride, hydrogen bromide, formate, esylate, tosylate, glycolate,acetate, xinafoate and hydrogen malonate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the x-ray diffraction pattern of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneglycolate prepared in accordance with Example 12.

FIG. 2 shows the IT-IR spectrum of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneglycolate prepared in accordance with Example 12.

FIG. 3 shows the x-ray diffraction pattern of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneacetate prepared in accordance with Example 15.

FIG. 4 shows the IT-IR spectrum of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneacetate prepared in accordance with Example 15.

FIG. 5 shows the x-ray diffraction pattern of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onexinafoate prepared in accordance with Example 18.

FIG. 6 shows the IT-IR spectrum of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onexinafoate prepared in accordance with Example 18.

FIG. 7 shows the x-ray diffraction pattern of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen malonate prepared in accordance with Example 21

FIG. 8 shows the IT-IR spectrum of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen malonate prepared in accordance with Example 21.

DETAILED DESCRIPTION

Terms used in the specification have the following meanings:

“Halogen” or “halo” as used herein denotes a element belonging to group17 (formerly group VII) of the Periodic Table of Elements, which may be,for example, fluorine, chlorine, bromine or iodine. Preferably halo orhalogen is fluorine or chlorine.

“C₁-C₁₀-alkyl” as used herein denotes straight chain or branched alkylthat contains one to ten carbon atoms. Preferably, C₁-C₁₀-alkyl isC₁-C₄-alkyl.

“Alkyl interrupted by one or more hetero atoms” denotes straight chainor branched alkyl e.g. C₂ to C₁₀ alkyl, in which one or more pairs ofcarbon atoms are linked by —O—, —NR—,—S—, —S(═O)— or —SO₂—, where R ishydrogen or C₁ to C₁₀ (preferably C₁ to C₄) alkyl. Preferred such groupsare alkoxyalkyl groups, preferably C₁-C₄-alkoxy-C₁-C₄-alkyl groups.

“C₂-C₁₀-alkenyl” as used herein denotes straight chain or branchedhydrocarbon chains that contain two to ten carbon atoms and one or morecarbon-carbon double bonds. Preferably “C₂-C₁₀-alkenyl” is“C₂-C₄-alkenyl”.

“5-, 6 or 7-membered carbocyclic ring” as used herein denotes acarbocyclic group having 5 to 7 ring carbon atoms, eithercycloaliphatic, such as a C₅-C₇-cycloalkyl, or aromatic, such as phenyl,which can be substituted by one or more, usually one or two, C₁-C₄-alkylgroups.

“C₅-C₇-cycloalkyl” as used herein denotes cycloalkyl having 5 to 7 ringcarbon atoms, for example cyclopentyl, cyclohexyl or cycloheptyl, any ofwhich can be substituted by one or more, usually one or two, C₁-C₄-alkylgroups.

“C₁-C₁₀-alkoxy” as used herein denotes straight chain or branched alkoxythat contains 1 to 10 carbon atoms. Preferably, C₁-C₁₀-alkoxy isC₁-C₄-alkoxy.

“C₁-C₁₀-alkoxycarbonyl” as used herein denotes C₁-C₁₀-alkoxy ashereinbefore defined linked through an oxygen atom thereof to a carbonylgroup.

“C₆-C₁₀-aryl” as used herein denotes a monovalent carbocyclic aromaticgroup that contains 6 to 10 carbon atoms and which may be, for example,a monocyclic group such as phenyl or a bicyclic group such as naphthyl.Preferably C₆-C₁₀-aryl is C₆-C₈-aryl, especially phenyl.

“4- to 10-membered heterocyclic ring having at least one ring nitrogen,oxygen or sulphur atom” as used herein may be, for example, pyrrole,pyrrolidine, pyrazole, imidazole, triazole, tetrazole, thiadiazole,oxazole, isoxazole, thiophene, thiazole, isothiazole, oxadiazole,pyridine, pyrazine, pyridazine, pyrimidine, piperidine, piperazine,triazine, oxazine, morpholino, quinoline, isoquinoline, naphthyridine,indane or indene. Preferred heterocyclic rings include thiazole,pyrrolidine, piperidine, azacycloheptane and isoxazole.

Throughout this specification and in the claims that follow, unless thecontext requires otherwise, the word “comprise”, or variations such as“comprises” or “comprising”, should be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

Preferred compounds of formula I include those wherein

R⁸, R⁹ and R¹⁰ are each H, R¹ is OH, R² and R³ are each H and

(i) R^(x) and R^(y) are both —CH₂—, and R⁴ and R⁷ are each CH₃O— and R⁵and R⁶ are each H;

(ii) R^(x) and R^(y) are both —CH₂—, and R⁴ and R⁷ are each H and R⁵ andR⁶ are each CH₃CH₂—;

(iii) R^(x) and R^(y) are both —CH₂—, and R⁴ and R⁷ are each H and R⁵and R⁶ are each CH₃—;

(iv) R^(x) and R^(y) are both —CH₂—, and R⁴ and R⁷ are each CH₃CH₂— andR⁵ and R⁶ are each H;

(v) R^(x) and R^(y) are both —CH₂—, and R⁴ and R⁷ are each H and R⁵ andR⁶ together denote —(CH₂)₄—;

(vi) R^(x) and R^(y) are both —CH₂—, and R⁴ and R⁷ are each H and R⁵ andR⁶ together denote —O(CH₂)₂O—-;

(vii) R^(x) and R^(y) are both —CH₂—, and R⁴ and R⁷ are each H and R⁵and R⁶ are each CH₃(CH₂)₃—;

(viii) R^(x) and R^(y) are both —CH₂—, and R⁴ and R⁷ are each H and R⁵and R⁶ are each CH₃(CH₂)₂—;

(ix) R^(x) and R^(y) are both —(CH₂)₂—, R⁴, R⁵, R⁶ and R⁷ are each H; or

(x) R^(x) and R^(y) are both —CH₂—, and R⁴ and R⁷ are each H and R⁵ andR⁶ are each CH₃OCH₂—.

Preferred compounds of formula I include namely:

8-hydroxy-5-[-1-hydroxy-2-(indan-2-ylamino)-ethyl]-1H-quinolin-2-oneglycolate,5-[-2-(5,6-dimethoxy-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-oneglycolate,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-3-methyl-1H-quinolin-2-oneglycolate,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-methoxy-methoxy-6-methyl-1H-quinolin-2-oneglycolate,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-6-methyl-1H-quinolin-2-oneglycolate,8-hydroxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-3,4-dihydro-1H-quinolin-2-oneglycolate,5-[(R)-2-(5,6-diethyl-2-methyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-oneglycolate,(S)-5-[2-(4,7-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onehydrochloride glycolate;

5-[(R)-1-hydroxy-2-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethyl]-8-hydroxy-1H-quinolin-2-onehydrochloride glycolate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onemaleate glycolate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onehydrochloride glycolate,(R)-8-hydroxy-5-[(S)-1-hydroxy-2-(4,5,6,7-tetramethyl-indan-2-ylamino)-ethyl]-1H-quinolin-2-oneglycolate,8-hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-indan-2-ylamino)-ethyl]-1H-quinolin-2-oneglycolate,5-[2-(5,6-diethyl-indan-2-ylamino)-ethyl]-8-hydroxy-1H-quinolin-2-oneglycolate,8-hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-ylamino)-ethyl]-1H-quinolin-2-oneglycolate,5-[(S)-2-(2,3,5,6,7,8-hexahydro-1H-cyclopenta-[b]naphthalen-2-ylamino)-1-hydroxy-ethyl┘-8-hydroxy-1H-quinolin-2-oneglycolate,8-hydroxy-5-[1-hydroxy-2-(indan-2-ylamino)-ethyl]-1H-quinolin-2-oneacetate,5-[2-(5,6-dimethoxy-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-oneacetate,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-3-methyl-1H-quinolin-2-oneacetate,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-methoxy-methoxy-6-methyl-1H-quinolin-2-oneacetate,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-6-methyl-1H-quinolin-2-oneacetate,8-hydroxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-3,4-dihydro-1H-quinolin-2-oneacetate,5-[(R)-2-(5,6-diethyl-2-methyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-oneacetate,(S)-5-[2-(4,7-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onehydrochloride acetate,5-[(R)-1-hydroxy-2-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethyl]-8-hydroxy-1H-quinolin-2-onehydrochloride acetate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onemaleate acetate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onehydrochloride acetate,(R)-8-hydroxy-5-[(S)-1-hydroxy-2-(4,5,6,7-tetramethyl-indan-2-ylamino)-ethyl]-1H-quinolin-2-oneacetate,8-hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-indan-2-ylamino)-ethyl]-1H-quinolin-2-oneacetate,5-[2-(5,6-diethyl-indan-2-ylamino)-ethyl]-8-hydroxy-1H-quinolin-2-oneacetate,8-hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-ylamino)-ethyl]-1H-quinolin-2-oneacetate,5-[(S)-2-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naph-thalen-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-oneacetate,8-hydroxy-5-[1-hydroxy-2-(indan-2-ylamino)-ethyl]-1H-quinolin-2-onexinafoate,5-[2-(5,6-dimethoxy-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onexinafoate,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-3-methyl-1H-quinolin-2-onexinafoate,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-methoxy-methoxy-6-methyl-1H-quinolin-2-onexinafoate,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-6-methyl-1H-quinolin-2-onexinafoate,8-hydroxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-3,4-dihydro-1H-quinolin-2-onexinafoate,5-[(R)-2-(5,6-diethyl-2-methyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onexinafoate,(S)-5-[2-(4,7-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onehydrochloride xinafoate,5-[(R)-1-hydroxy-2-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethyl]-8-hydroxy-1H-quinolin-2-onehydrochloride xinafoate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onemaleate xinafoate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onehydrochloride xinafoate,(R)-8-hydroxy-5-[(S)-1-hydroxy-2-(4,5,6,7-tetramethyl-indan-2-ylamino)-ethyl]-1H-quinolin-2-onexinafoate,8-hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-indan-2-ylamino)-ethyl]-1H-quinolin-2-onexinafoate,5-[2-(5,6-diethyl-indan-2-ylamino)-ethyl]-8-hydroxy-1H-quinolin-2-onexinafoate,8-hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-ylamino)-ethyl]-1H-quinolin-2-onexinafoate,5-[(S)-2-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naph-thalen-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onexinafoate,8-hydroxy-5-[1-hydroxy-2-(indan-2-ylamino)-ethyl]-1H-quinolin-2-onehydrogen malonate,5-[2-(5,6-dimethoxy-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onehydrogen malonate,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-3-methyl-1H-quinolin-2-onehydrogen malonate,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-methoxy-methoxy-6-methyl-1H-quinolin-2-onehydrogen malonate,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-6-methyl-1H-quinolin-2-onehydrogen malonate,8-hydroxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-3,4-dihydro-1H-quinolin-2-onehydrogen malonate,5-[(R)-2-(5,6-diethyl-2-methyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one hydrogen malonate,(S)-5-[2-(4,7-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onehydrochloride hydrogen malonate,5-[(R)-1-hydroxy-2-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethyl]-8-hydroxy-1H-quinolin-2-onehydrochloride hydrogen malonate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onemaleate hydrogen malonate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onehydrochloride hydrogen malonate,(R)-8-hydroxy-5-[(S)-1-hydroxy-2-(4,5,6,7-tetramethyl-indan-2-ylamino)-ethyl]-1H-quinolin-2-onehydrogen malonate,8-hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-indan-2-ylamino)-ethyl]-1H-quinolin-2-onehydrogen malonate,5-[2-(5,6-diethyl-indan-2-ylamino)-ethyl]-8-hydroxy-1H-quinolin-2-onehydrogen malonate,8-hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-ylamino)-ethyl]-1H-quinolin-2-onehydrogen malonate, and5-[(S)-2-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naph-thalen-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onehydrogen malonate.

Especially preferred compounds of formula I are compounds of formula II

where A is selected from the group consisting of hydrogen succinate,fumarate, hippurate, mesylate, hydrogen sulphate, hydrogen tartrate,hydrogen chloride, hydrogen bromide, formate, esylate, tosylate,glycolate, acetate, xinafoate and hydrogen malonate, namely(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen succinate,(R)-5-[-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onefumarate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehippurate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onemesylate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen sulfate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen tartrate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen chloride,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen bromide,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneformate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneesylate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onetosylate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneglycolate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneacetate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onexinafoate and(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen malonate.

The free form of compounds of formula I may be prepared by using theprocedures described in international patent application WO 2000/075114,the contents of which is incorporated herein by reference. Compounds offormula I are prepared by reacting the free base with the relevant acid,or analogously as described in the Examples using processes known in theart for forming acid addition salts from secondary amines. When A ishydrogen succinate, fumarate, hippurate, mesylate, hydrogen sulphate,hydrogen tartrate, hydrogen chloride, hydrogen bromide, formate, esylateor tosylate the relevant acid is succinic acid, fumaric acid, hippuricacid, methanesulfonic acid, sulfuric acid, (+)-L-tartaric acid,hydrochloric acid, hydrobromic acid, formic acid, ethansulfonic acid andp-toluenesulfonic acid respectively. When A is glycolate, glycolatesalts of the invention are prepared by reacting the free base withglycolic acid, or analogously as described in the Examples usingprocesses known in the art for forming glycolic acid addition salts fromsecondary amines. When A is acetate, acetate salts of the invention areprepared by reacting the free base with acetic acid, or analogously asdescribed in the Examples using processes known in the art for formingacetic acid addition salts from secondary amines. When A is xinafoate,xinafoate salts of the invention are prepared by reacting the free basewith 1-hydroxy-2-naphthoic acid, or analogously as described in theExamples using processes known in the art for forming1-hydroxy-2-naphthoic acid addition salts from secondary amines. When Ais hydrogen malonate, hydrogen malonate salts of the invention areprepared by reacting the free base with malonic acid, or analogously asdescribed in the Examples using processes known in the art for formingmalonic acid addition salts from secondary amines.

In a second aspect the invention provides a pharmaceutical compositioncomprising, as active ingredient, an effective amount of a compound offormula I, optionally together with a pharmaceutically acceptablecarrier. Preferably the composition is in inhalable form.

In a third aspect the invention concerns the use of a compound offormula I for the preparation of a medicament for the treatment of aninflammatory or obstructive airways disease.

In a fourth aspect the invention provides a process for preparing acompound of formula I comprising reacting the free base with therelevant acid.

Accordingly the process of the present invention comprises:

(i) for the preparation of compounds of formula I where A is hydrogensuccinate, reacting the free base with succinic acid;

(ii) for the preparation of compounds of formula I where A is fumarate,reacting the free base with fumaric acid;

(iii) for the preparation of compounds of formula I where A ishippurate, reacting the free base with hippuric acid;

(iv) for the preparation of compounds of formula I where A is mesylate,reacting the free base with methanesulfonic acid;

(v) for the preparation of compounds of formula I where A is hydrogensulphate, reacting the free base with sulfuric acid;

(vi) for the preparation of compounds of formula I where A is hydrogentartrate, reacting the free base with (+)-L-tartaric;

(vii) for the preparation of compounds of formula I where A is hydrogenchloride, reacting the free base with hydrochloric acid;

(viii) for the preparation of compounds of formula I where A is hydrogenbromide, reacting the free base with hydrobromic acid;

(ix) for the preparation of compounds of formula I where A is formate,reacting the free base with formic acid;

(x) for the preparation of compounds of formula I where A is esylate,reacting the free base with ethansulfonic acid;

(xi) for the preparation of compounds of formula I where A is tosylate,reacting the free base with p-toluenesulfonic acid;

(xii) for the preparation of compounds of formula I where A isglycolate, reacting the free base with glycolic acid;

(xiii) for the preparation of compounds of formula I where A is acetate,reacting the free base with acetic acid;

(xiv) for the preparation of compounds of formula I where A isxinafoate, reacting the free base with 1-hydroxy-2-naphthoic acid; or

(xv) for the preparation of compounds of formula I where A is, hydrogenmalonate, reacting the free base with malonic acid.

The compounds of formula I, hereinafter referred to alternatively as“agents of the invention”, have good β₂-adrenoreceptor agonist activityand are useful as pharmaceuticals. The β₂-agonist activity, onset ofaction and duration of action of the agents of the invention may betested using the guinea pig tracheal strip in vitro assay according tothe procedure of R. A. Coleman and A. T. Nials, J. Pharmacol. Methods(1989), 21(1), 71-86. The binding potency and selectivity for theβ₂-adrenoreceptor relative to the β₁-adrenoreceptor can be measured by aclassical filtration binding assay according to the procedure of CurrentProtocols in Pharmacology (S. J. Enna (editor-in-chief) et al, JohnWiley & Son, Inc, 1998), or by cAMP determination in cells expressingβ₂- or β₁-adrenoceptor, according to the procedure of B. January et al,British J. Pharmacol. 123: 701-711 (1998).

The agents of the invention commonly have a rapid onset of action andhave a prolonged stimulating action on the β₂-adrenoreceptor. Theytypically have Ki (β₂) values of the order of 0.1 to 1000 nM, durationsof action of the order of 1 to greater than 12 hours or even 24 hours,and having binding selectivities for the β₂-adrenoreceptor relative tothe f31-adreno-receptor from 1.5 to 500.

Having regard to their β₂-agonist activity, the agents of the inventionare suitable for use in the treatment of any condition which isprevented or alleviated by activation of the β₂-adreno-receptor. In viewof their long acting selective β₂-agonist activity, the agents of theinvention are useful in the relaxation of bronchial smooth muscle andthe relief of bronchoconstriction. Relief of bronchoconstriction can bemeasured in models such as the in vivo plethysmography models of Chonget al, J. Pharmacol. Toxicol. Methods 1998, 39, 163-168, Hammelmann etal, Am. J. Respir. Crit. Care Med., 1997, 156, 766-775 and analogousmodels. The agents of the invention are therefore useful in thetreatment of obstructive or inflammatory airways diseases. In view oftheir long duration of action, it is possible to administer the agentsof the invention once-a-day in the treatment of such diseases. Inanother aspect, agents of the invention commonly exhibit characteristicsindicating a low incidence of side effects commonly encountered withβ₂-agonists such as tachycardia, tremor and restlessness, such agentsaccordingly being suitable for use in on demand (rescue) treatment aswell as prophylactic treatment of obstructive or inflammatory airwaysdiseases.

The corresponding maleate salt of the compound of formula II, namely(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onemaleate, has tested favourably in the clinic for the treatment of asthmaand chronic obstructive pulmonary disease. Alternative salts have beeninvestigated to address issues noted in formulating the compound foradministered by inhalation, or at least provide a useful alternative tomaleate salts.

Surprisingly, compounds of formula I have been found to present a goodcrystallinity and retain minimal residual solvent. They have lowsolubility in ethanol which is especially advantageous in inhalationproducts that contain ethanol. Agents of the invention may prevent orminimise the cough that certain patients have exhibited onadministration, particularly first administration, of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onemaleate. Glycolate salts of formula I, including(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneglycolate, have been found to present a good crystallinity and isanhydrous. They are substantially not hydroscopic and have a clearmelting peak at 140-250° C. They are especially stable, before and aftermicronisation, with or without excipients, and with and withoutmoisture. They have low solubility in ethanol which is especiallyadvantageous in inhalation products that contain ethanol. They also hasgood melting onset, no presence of residual solvent, a goodcrystallinity and no change of crystalline form after equilibration for1 day at 25° C. in water, ethanol and isopropanol. Acetate salts offormula I, including(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneacetate, have been found to present a good crystallinity and retainminimal residual solvent. They are substantially not hydroscopic andhave a clear melting peak at 140-250° C. They are especially stable,before and after micronisation, with or without excipients, and with andwithout moisture. They have low solubility in ethanol which isespecially advantageous in inhalation products that contain ethanol.They also has good melting onset, no presence of residual solvent, andno change of crystalline form after equilibration for 1 day at 25° C. inwater, ethanol and isopropanol. Xinafoate salts of formula I, including(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onexinafoate, have been found to present a good crystallinity and retainminimal residual solvent. They are substantially not hydroscopic andhave a clear melting peak at 140-250° C. They are especially stable,before and after micronisation, with or without excipients, and with andwithout moisture. They have low solubility in ethanol which isespecially advantageous in inhalation products that contain ethanol.They also has good melting onset, no presence of residual solvent, andno change of crystalline form after equilibration for 1 day at 25° C. inwater, ethanol and isopropanol. Malonate salts of formula I, including(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen malonate, have been found to present a good crystallinity andretain minimal residual solvent. They are substantially not hydroscopicand have a clear melting peak at 140-250° C. They are especially stable,before and after micronisation, with or without excipients, and with andwithout moisture. They have low solubility in ethanol which isespecially advantageous in inhalation products that contain ethanol.They also has good melting onset, no presence of residual solvent, andno change of crystalline form after equilibration for 1 day at 25° C. inwater, ethanol and isopropanol.

Given their anti-inflammatory activity, the agents of the invention areuseful in the treatment of inflammatory conditions, particularlyinflammatory or obstructive airways diseases. Treatment in accordancewith the invention may be symptomatic or prophylactic.

Inflammatory or obstructive airways diseases to which the presentinvention is applicable include asthma of whatever type or genesisincluding both intrinsic (non-allergic) asthma and extrinsic (allergic)asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma,exercise-induced asthma, occupational asthma and asthma inducedfollowing bacterial infection. Treatment of asthma is also to beunderstood as embracing treatment of subjects, e.g. of less than 4 or 5years of age, exhibiting wheezing symptoms and diagnosed or diagnosableas “wheezy infants”, an established patient category of major medicalconcern and now often identified as incipient or early-phase asthmatics.(For convenience this particular asthmatic condition is referred to as“wheezy-infant syndrome”.)

Prophylactic efficacy in the treatment of asthma will be evidenced byreduced frequency or severity of symptomatic attack, e.g. of acuteasthmatic or bronchoconstrictor attack, improvement in lung function orimproved airways hyperreactivity. It may further be evidenced by reducedrequirement for other, symptomatic therapy, i.e. therapy for or intendedto restrict or abort symptomatic attack when it occurs, for exampleanti-inflammatory (e.g. cortico-steroid) or bronchodilatory.Prophylactic benefit in asthma may in particular be apparent in subjectsprone to “morning dipping”. “Morning dipping” is a recognised asthmaticsyndrome, common to a substantial percentage of asthmatics andcharacterised by asthma attack, e.g. between the hours of about 4 to 6am, i.e. at a time normally substantially distant from any previouslyadministered symptomatic asthma therapy.

Other inflammatory or obstructive airways diseases and conditions towhich the present invention is applicable include acute lung injury(ALI), adult/acute respiratory distress syndrome (ARDS), chronicobstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema,as well as exacerbation of airways hyperreactivity consequent to otherdrug therapy, in particular other inhaled drug therapy. The invention isalso applicable to the treatment of bronchitis of whatever type orgenesis including, e.g., acute, arachidic, catarrhal, croupus, chronicor phthinoid bronchitis. Further inflammatory or obstructive airwaysdiseases to which the present invention is applicable includepneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

Having regard to their anti-inflammatory activity, in particular inrelation to inhibition of eosinophil activation, the agents of theinvention are also useful in the treatment of eosinophil relateddisorders, e.g. eosinophilia, in particular eosinophil related disordersof the airways (e.g. involving morbid eosinophilic infiltration ofpulmonary tissues) including hypereosinophilia as it effects the airwaysand/or lungs as well as, for example, eosinophil-related disorders ofthe airways consequential or concomitant to Löffler's syndrome,eosinophilic pneumonia, parasitic (in particular metazoan) infestation(including tropical eosinophilia), bronchopulmonary aspergillosis,polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilicgranuloma and eosinophil-related disorders affecting the airwaysoccasioned by drug-reaction.

The agents of the invention are also useful in the treatment ofinflammatory conditions of the skin, for example psoriasis, contactdermatitis, atopic dermatitis, alopecia areata, erythema multiforma,dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivityangiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus,epidermolysis bullosa acquisita, and other inflammatory conditions ofthe skin.

The agents of the invention may also be used for the treatment of otherdiseases or conditions, in particular diseases or conditions having aninflammatory component, for example, treatment of diseases andconditions of the eye such as conjunctivitis, keratoconjunctivitissicca, and vernal conjunctivitis, diseases affecting the nose includingallergic rhinitis, diseases of the joints such as rheumatoid arthritisand inflammatory bowel disease such as ulcerative colitis and Crohn'sdisease.

Further, agents of the invention may also be used for the treatment ofcystic fibrosis, pulmonary hypertension and pulmonary fibrosis.

The agents of the invention are also useful as co-therapeutic agents foruse in conjunction with other drug substances for treatment of airwaysdiseases, particularly anti-inflammatory, bronchodilatory,antihistaminic/anti-allergic or anti-tussive drug substances,particularly in the treatment of obstructive or inflammatory airwaysdiseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Theagents of the invention may be mixed with one, two, three or more otherdrugs in a fixed pharmaceutical composition or they may be administeredseparately, before, simultaneously with or after the other drug(s).

Such anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide, dexamethasone, flunisolide,mometasone furoate and triamcinolone but also compounds described in WO02/00679, WO 02/88167, WO 02/12266, WO 02/100879 or WO 02/00679,especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60,67, 72, 73, 90, 99 and 101, (including salts or derivatives thereof suchas sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates,propionates, dihydrogen phosphates, palmitates, pivalates or furoates,and, where possible, hydrates) and non-steroidal steroid agonists suchas those described in WO 00/00531, WO 02/10143, WO 03/082280, WO03/082787, WO 03/104195, WO 04/005229; dopamine agonists such asbromocriptine, cabergolin, alpha-dihydroergocryptine, lisuride,pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid andviozan (including pharmaceutically acceptable salts thereof such assalts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoricacid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid,lactic acid, citric acid, tartaric acid and maleic acid); LTB4antagonists such as BIIL 284, CP-195543, DPC11870, LTB4 ethanolamide, LY293111, LY 255283, CGS025019C, CP-195543, ONO-4057, SB 209247, SC-53228and those described in U.S. Pat. No. 5,451,700 and WO 04/108720; LTD4antagonists such as montelukast, pranlukast, zafirlukast, accolate,SR2640, Wy-48,252, ICI 198615, MK-571, LY-171883, Ro 24-5913 andL-648051; dopamine receptor agonists such as cabergoline, bromocriptine,ropinirole and4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)-propyl]sulfonyl]ethyl]-amino]ethyl]-2(3H)-benzothiazoloneand pharmaceutically acceptable salts thereof (the hydrochloride beingViozan®—AstraZeneca); PDE4 inhibitors such as cilomilast (Ariflo®GlaxoSmithKline), Roflumilast (Byk Gulden),V-11294A (Napp), BAY19-8004(Bayer), SCH-351591 (Schering-Plough), Arofylline (AlmirallProdesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica),CDC-801 (Celgene), SelCID(TM) CC-10004 (Celgene), VM554/UM565(Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), GRC 3886(Oglemilast, Glenmark), WO 92/19594, WO 93/19749, WO 93/19750, WO93/19751, WO 98/18796, WO 99/16766, WO 01/13953, WO 03/39544, WO03/104204, WO 03/104205, WO 04/000814, WO 04/000839 and WO 04/005258(Merck), WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO04/018431, WO 04/018449, WO 04/018450, WO 04/018451, WO 04/018457, WO04/018465, WO 04/019944, WO 04/019945, WO 04/045607, WO 04/037805, WO04/063197, WO 04/103998, WO 04/111044, WO 05/012252, WO 05012253, WO05/013995, WO 05/030212, WO 05/030725, WO 05/087744, WO 05/087745, WO05/087749 and WO 05/090345 (including physiologically acceptable acidaddition salts thereof such as salts of hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, methane-sulphonic acid, aceticacid, fumaric acid, succinic acid, lactic acid, citric acid, tartaricacid and maleic acid); A2a agonists such as those described in EP409595A2, EP 1052264, EP 1241176, WO 94/17090, WO 96/02543, WO 96/02553,WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO 99/38877, WO99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO02/96462, WO 03/086408, WO 04/039762, WO 04/039766, WO 04/045618 and WO04/046083; and A2b antagonists such as those described in WO 02/42298and WO 03/042214.

Such bronchodilatory drugs include anticholinergic or antimuscarinicagents, in particular ipratropium bromide, oxitropium bromide,tiotropium salts, glycopyrrolate, CHF 4226 (Chiesi) and SVT-40776, butalso those described in EP 424021, U.S. Pat. No. 3,714,357, U.S. Pat.No. 5,171,744, US 2005/171147, US 2005/182091, WO 01/04118, WO 02/00652,WO 02/51841, WO 02/53564, WO 03/00840, WO 03/33495, WO 03/53966, WO03/87094, WO 04/18422, WO 04/05285, WO 04/96800, WO 05/77361 and WO06/48225.

Suitable bronchodilatory also include beta-2 adrenoceptor agonists suchas albuterol (salbutamol), metaproterenol, terbutaline, salmeterol,fenoterol, procaterol, and especially, formoterol, carmoterol, TA-2005,GSK159797 and pharmaceutically acceptable salts thereof, and alsocompounds of EP 147719, EP 1440966, EP 1460064, EP 1477167, EP 1574501,JP 05025045, JP 2005187357, US 2002/0055651, US 2004/0242622, US2004/0229904, US 2005/0133417, US 2005/5159448, US 2005/5159448, US2005/171147, US 2005/182091, US 2005/182092, US 2005/209227, US2005/256115, US 2005/277632, US 2005/272769, US 2005/239778, US2005/215542, US 2005/215590, US 2006/19991, US 2006/58530, WO 93/18007,WO 99/64035, WO 01/42193, WO 01/83462, WO 02/66422, WO 02/70490, WO02/76933, WO 03/24439, WO 03/42160, WO 03/42164, WO 03/72539, WO03/91204, WO 03/99764, WO 04/16578, WO 04/16601,WO 04/22547, WO04/32921, WO 04/33412, WO 04/37768, WO 04/37773, WO 04/37807, WO04/39762, WO 04/39766, WO 04/45618 WO 04/46083 , WO 04/80964, WO04/087142, WO 04/89892, WO 04/108675, WO 04/108676, WO 05/33121, WO05/40103, WO 05/44787, WO 05/58867, WO 05/65650, WO 05/66140, WO05/70908, WO 05/74924, WO 05/77361, WO 05/90288, WO 05/92860, WO05/92887, WO 05/90287, WO 05/95328, WO 05/102350, WO 06/56471, WO06/74897 or WO 06/8173.

Suitable dual anti-inflammatory and bronchodilatory drugs include dualbeta-2 adrenoceptor agonist/muscarinic antagonists such as thosedisclosed in US 2004/0167167, US 2004/0242622, US 2005/182092, US2005/256114, US 2006/35933, WO 04/74246, WO 04/74812, WO 04/89892 and WO06/23475.

Suitable antihistaminic/anti-allergic drug substances includeacetaminophen, activastine, astemizole, azelastin, bamipin, cetirizinehydrochloride, cexchloropheniramine, chlorophenoxamine, clemastinefumarate, desloratidine, dimenhydrinate, dimetinden, diphenhydramine,doxylamine, ebastine, emedastin, epinastine, fexofenadine hydrochloride,ketotifen, levocetirizine, levocabastin, loratidine, meclizine,mizolastine, pheniramine, promethazine and tefenadine, as well as thosedisclosed in JP 2004107299, WO 03/099807 and WO 04/026841 (including anypharmacologically acceptable acid addition salts thereof which mayexist).

Combinations of the agents of the invention and steroids, PDE4inhibitors or LTD4 antagonists are particularly suitable for use in thetreatment of asthma. Whereas combinations of the agents of the inventionand anticholinergic or antimuscarinic agents, PDE4 inhibitors, LTB4antagonists are particularly suitable for use in the treatment of COPD.

In accordance with the foregoing, the invention provides a method forthe treatment of an inflammatory condition, particularly an inflammatoryor obstructive airways disease, which comprises administering to asubject, particularly a human subject, in need thereof an effectiveamount of a compound of formula I as hereinbefore described. Theinvention also provides the use of a compound of formula I ashereinbefore described for the manufacture of a medicament for thetreatment of an inflammatory condition, particularly an inflammatory orobstructive airways disease.

The agents of the invention may be administered by any appropriateroute, e.g. orally, for example in the form of a tablet or capsule;parenterally, for example intravenously; by inhalation, for example inthe treatment of inflammatory or obstructive airways disease;intranasally, for example in the treatment of allergic rhinitis;topically to the skin, for example in the treatment of atopicdermatitis; or rectally, for example in the treatment of inflammatorybowel disease.

Accordingly the invention provides a pharmaceutical compositioncomprising as active ingredient a compound of formula I, optionallytogether with a pharmaceutically acceptable diluent or carrier therefor.The invention also provides a pharmaceutical composition comprising asactive ingredient a compound of formula I and one, two, three or moreanti-inflammatory, bronchodilatory, antihistaminic/anti-allergic oranti-tussive drug substances, optionally together with apharmaceutically acceptable diluent or carrier therefor. Suchcompositions may be prepared using conventional diluents or excipientsand techniques known in the galenic art.

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number or layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof. Excipients which may be used include, forexample, water, pharmaceutically acceptable organic solvents such asparaffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut orsesame oil), mono- or polyfunctional alcohols (e.g. ethanol orglycerol), carriers such as e.g. natural mineral powders (e.g. kaolins,clays, talc, chalk), synthetic mineral powders (e.g. highly dispersedsilicic acid and silicates), sugars (e.g. cane sugar, lactose andglucose), emulsifiers (e. g. lignin, spent sulphite liquors,methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g.magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

When the composition comprises an aerosol formulation, it preferablycontains, for example, a hydro-fluoro-alkane (HFA) propellant such asHFA134a or HFA227 or a mixture of these, and may contain one or moreco-solvents known in the art such as ethanol (up to 20% by weight),and/or one or more surfactants such as oleic acid or sorbitan trioleate,and/or one or more bulking agents such as lactose. When the compositioncomprises a dry powder formulation, it preferably contains, for example,an agent of the invention having a particle diameter up to 10 microns,optionally together with a diluent or carrier, such as lactose, of thedesired particle size distribution and a compound that helps to protectagainst product performance deterioration due to moisture e.g. magnesiumstearate, typically 0.05-2.0% magnesium stearate. When the compositioncomprises a nebulised formulation, it preferably contains, for example,an agent of the invention either dissolved, or suspended, in a vehiclecontaining water, a co-solvent such as ethanol or propylene glycol and astabiliser, which may be a surfactant.

The invention includes (A) an agent of the invention in inhalable form,e.g. in an aerosol or other atomisable composition or in inhalableparticulate, e.g. micronised, form, (B) an inhalable medicamentcomprising an agent of the invention in inhalable form; (C) apharmaceutical product comprising an agent of the invention in inhalableform in association with an inhalation device; and (D) an inhalationdevice containing an agent of the invention in inhalable form.

A suitable device for delivery of dry powder in encapsulated form isdescribed in U.S. Pat. No. 3,991,761 (including the AEROLIZER™ device)or WO 05/113042, while suitable MDDPI devices include those described inWO 97/20589 (including the CERTIHALER™ device), WO 97/30743 (includingthe TWISTHALER™ device) and WO 05/37353 (including the GYROHALER™device).

Dosages of agents of the invention employed in practising the presentinvention will of course vary depending, for example, on the particularcondition to be treated, the effect desired and the mode ofadministration. In general, suitable daily dosages for administration byinhalation are of the order of 0.005 to 10 mg, while for oraladministration suitable daily doses are of the order of 0.05 to 100 mg.

The invention is illustrated by the following Examples.

EXAMPLES Example 1 Preparation of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen succinate

A suspension of 2.312 g(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onebase (5.890 mmoles) and 0.695 g succinic acid (5.890 mmoles) in 50 mlisopropanol is heated to 80° C. The resulting almost clear solution isstirred at 80° C. Crystallization takes place spontaneously after ca. 5minutes. The suspension is allowed to cool slowly and stirred at roomtemperature for 18 hours. The salt is collected after filtration andwashing with 7 ml isopropanol. The crystals are dried for 20 hours at70° C. and ca. 10 mbar.

Yield: 2.89 g white powder (96.3%)

Elemental analysis:

Calc.: 65.87% C; 6.71% H; 5.49% N; 21.93% O

Found: 65.49% C; 6.75% H; 5.56% N; 21.86% O

Example 2 Preparation of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onefumarate

A suspension of 2.208 g(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onebase (5.625 mmoles) in 20 ml methanol is heated to 50° C. A solution of0.326 g fumaric acid (2.81 mmoles) in 5 ml methanol is dropwise added tothe suspension at constant flow rate, over 10 minutes. The resultingsolution is stirred at 50° C. Crystallization takes then spontaneouslyplace after ca. 10 minutes. The suspension is allowed to cool andstirred for 3 hours at room temperature. The mixture is filtered. Thecrystals are washed with 7 ml methanol and dried first for 20 hours at60° C. and ca. 10 mbar and further for 2 h at 60° C. and ca. 1 mbar.Yield: 2.19 g white powder (86.4%)

Elemental analysis:

Calc.: 69.31% C; 6.71% H; 6.22% N; 17.76% O

Found: 67.69% C; 6.62% H; 6.35% N; 19.00% O

Example 3 Preparation of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-auinolin-2-onehippurate

A suspension of 1.95 g(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onebase (4.968 mmoles) in 28.5 ml methanol is heated to 45° C. 0.89 ghippuric acid (4.968 mmoles) are added in portions over 5 minutes at45-50° C. The resulting almost complete solution, is further stirred at50° C. Spontaneous crystallization occurs after ca 5 minutes. 15 mlmethanol are added to the very thick mixture. The suspension is allowedto cool and stirred for 4 hours at room temperature. The suspension isfiltered and the salt is washed with 10 ml methanol. The crystals aredried first for 20 hours at 70° C. and ca. 10 mbar and further for 4hours at 60° C. and ca. 1 mbar. Yield: 2.15 g white powder (75.7%)

Elemental analysis:

Calc.: 69.33% C; 6.52% H; 7.35% N; 16.79% O

Found: 69.20% C; 6.67% H; 7.35% N; 16.85% O

Example 4 Preparation of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onemesylate monohydrate

A suspension of 2.139 g(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onebase (5.45 mmoles) in 20 ml water is heated to 70° C. A solution of0.524 g methanesulfonic acid (5.45 mmoles) in 5 ml water is addeddropwise over ca. 2 minutes. At the end of the addition the notdissolved solid consists of aggregates. A white good stirrablesuspension is then formed after ca. 10 minutes. at 70° C. The mixture isslowly cooled to 25° C. and stirred for 20 hours at room temperature.After filtration, the solid is washed with 5 ml water and 10 ml acetoneand dried for 20 hours at 70° C. and ca. 10 mbar. Yield: 2.40 g whitepowder (86.9%)

Elemental analysis:

Calc.: 59.27% C; 6.76% H; 5.53% N; 6.33% S; 22.11% O

Found: 59.24% C; 6.74% H; 5.46% N; 6.33% S; 22.36% O

Water assay: 3.7% (m/m)

Example 5 Preparation of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen sulfate

2.063 g(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onebase (5.256 mmoles) are dissolved in 12 ml acetic acid at 50° C. Asolution of 0.526 g sulfuric acid 98% (5.256 mmoles) in 4 ml acetic acidis adder dropwise, at constant flow rate, over 5 minutes. The clearsolution is allowed to cool. Crystallization takes spontaneously placeat ca. 35° C. The suspension is stirred for 18 h at room temperature andthen filtered. The crystals are washed with 4 ml acetic acid and 10 mlethylacetate. The salt is dried first for 20 hours at 70° C. and ca. 10mbar and then for 2 hours at 60° C. and ca. 1 mbar. Yield: 2.31 g whitepowder (86.9%)

Elemental analysis:

Calc.: 58.76% C; 6.16% H; 5.71% N; 6.54% S; 22.83% O

Found: 57.22% C; 6.05% H; 5.31% N; 6.69% S; 24.55% O

Example 6 Preparation of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen tartrate

A suspension of 2.0 g(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onebase (5.10 mmoles) in 14 ml isopropanol is heated at 50° C. Then asolution of 0.77 g L (+) tartaric acid (5.10 mmoles) in 7.7 mlisopropanol is dropwise added over ca. 2 minutes. The suspension isstirred at 50° C. for 15 hours. The white suspension is cooled to ca.25° C. and filtered. The salt is washed with 10 ml isopropanol and driedfor 18 hours/50° C./ca. 10 mbar and for 2 hours at 60° C./ca. 1 mbar.Yield: 2.33 g white powder (84.27%)

Elemental analysis:

Calc.: 61.98% C; 6.32% H; 5.16% N; 26.54% O

Found: 59.02% C; 6.41% H; 5.47% N; 23.30% O

Example 7 Preparation of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrochloride

A suspension of 3.78 g(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onebase (9.63 mmoles) in 36.5 ml methanol is heated to 50° C. A solution of0.949 g hydrochloric acid 37% (9.63 mmoles) in 10 ml methanol is addeddropwise, over 15 minutes. The resulting clear solution is allowed tocool. Crystallization begins spontaneously at 40° C. The suspension isstirred at room temperature for 17 hours. After filtration the salt iswashed with 7 ml methanol. The crystals are dried for 16 hours at 50°C./ca. 10 mbar and for 2 hours at 50° C. and ca. 1 mbar. Yield: 2.33 gwhite powder (84.27%)

Elemental analysis:

Calc.: 67.20% C; 6.81% H; 6.53% N; 8.26% Cl; 11.19% O

Found: 66.79% C; 6.88% H; 6.55% N; 7.99% Cl; 11.81% O

Example 8 Preparation of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrobromide

A suspension of 1.93 g(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onebase (4.92 mmoles) in 13.5 ml methanol is heated to 50° C., A solutionof 0.829 g hydrobromic acid 48% (4.92 mmoles) in 5 ml methanol isdropwise added over 15 minutes. The resulting very thick suspension isdiluted with 43 ml methanol and allowed to cool. After stirring for 3hours at room temperature the precipitate is filtered. The filter cakeis washed with 5 ml methanol. The crystals are dried for 16 hours at 50°C./ca. 10 mbar and for 2 hours at 50° C. and ca. 1 mbar. Yield: 2.33 gwhite powder (84.27%)

Elemental analysis:

Calc.: 60.89% C; 6.17% H; 5.92% N; 16.88% Br; 10.14% O

Found: 60.55% C; 6.09% H; 6.00% N; 16.37% Br; 10.43% O

Example 9 Preparation of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneformate

A suspension of 2.00 g(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onebase (5.1 mmoles) in 15 ml methanol is heated to 50° C. 0.24 g formicacid (5.2 mmoles) are dropwise added. The dropping funnel is rinsed with5 ml methanol. The resulting clear solution is allowed to slowly cool.Crystallization starts spontaneously at ca. 47° C. The mixture isstirred at ca. 25° c for 15 hours and filtered. The filter cake iswashed with 4 ml methanol. The salt is dried for 20 hours at 50° C./ca.10 mbar and for 3 hours at 70° C. and ca. 1 mbar. Yield: 1.77 g whitepowder (79.37%)

Elemental analysis:

Calc.: 68.47% C; 6.90% H; 6.39% N; 18.24% O

Found: 68.30% C; 6.96% H; 6.38% N; 18.46% O

Example 10 Preparation of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneesylate

2.00 g(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onebase (5.1 mmoles) are dissolved in 8 ml dimethylsulfoxide at 50° C. Thesolution is cooled to 25° C. 0.595 g ethanesulfonic acid (5.4 mmoles)are added dropwise over 5 minutes. and the dropping funnel is rinsedwith 1 ml DMSO. Then 18 ml water are added at constant flow rate, overca. 30 min. The resulting thick suspension is diluted with 8 ml waterand stirred over night at room temperature. The mixture is filtered andthe solid washed with 10 ml water. The product is dried for 3 hours at50° C./ca. 10 mbar and for 3 hours at 70° C. and ca. 1 mbar. Yield: 1.56g white powder, Karl Fischer: 3.2% m/m H₂O

Elemental analysis: (calc. for the monohydrate)

Calc.: 59.98% C; 6.97% H; 5.38% N; 6.16% S; 21.51% O

Found: 61.70% C; 6.73% H; 5.69% N; 6.36% S; 19.13% O

Example 11 Preparation of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onetosylate

A mixture of 2.00 g(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onebase (5.1 mmoles) and 0.98 g p-toluenesulfonic acid monohydrate (5.1mmoles) in 30 ml ethylacetate is heated to 60° C. During heating theinitially sticky yellow amorphous mass, turns to a white, good stirrablesuspension. The suspension is allowed to cool and stirred at roomtemperature over night. The crystals are collected after filtration andwashing with ethylacetate. The salt is dried for ca. 20 hours at 50° C.and ca. 10 mbar. Yield: 2.73 g off white powder (94.8%)

Elemental analysis:

Calc.: 65.94% C; 6.43% H; 4.96% N; 5.68% S; 17.00% O

Found: 64.51% C; 6.42% H; 5.01% N; 5.60% S; 18.60% O

Example 12 Preparation of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneglycolate

A suspension of 2.075 g(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onebase (5.286 mmoles) in 25 ml methanol is heated to 50° C. A solution of0.402 g glycolic acid (5.286 mmoles) in 5 ml methanol is added dropwiseover 7 minutes. The resulting clear solution is stirred at 50° C.Crystallization takes spontaneously place after ca 15 minutes. The whitesuspension is allowed to cool to room temperature and stirred over nightat ca. 25° C. After 18 hours the salt is filtered. The filter cake iswashed with 7 ml methanol and dried first 20 hours at 60° C. and ca. 10mbar and then 2 hours at 60° C. and ca. 1 mbar.

Yield: 1.77 g white powder (71.37%).

Elementary analysis:

Calc.: 66.65% C; 6.88% H; 5.98% N; 20.49% O

Found: 66.46% C; 6.80% H; 6.19% N; 20.33% O

Example 13 Characterisation of Salt by X-ray Powder Diffraction

The X-ray diffraction pattern of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneglycolate prepared in accordance with Example 12 is measured using aSCINTAG™ X-ray diffractometer with a CuK alpha radiation source. TheX-ray diffraction pattern thus determined is shown in FIG. 1 andrepresented in Table I below by the reflection lines and intensities ofthe most important lines.

TABLE I X-ray diffraction lines and intensities for the glycolate saltRelative 2θ (°) d-spacings (Å) intensity 2.8 31.28 S 5.7 15.39 M 12.27.22 M 14.5 6.10 M 15.2 5.84 L 16.8 5.27 L 17.4 5.08 L 18.3 4.82 L 19.24.62 L 19.7 4.51 L 20.4 4.35 L 21.4 4.14 L 23.3 3.82 M 25.4 3.50 L 26.43.38 L

The XRPD pattern shows a strong diffraction peak at 2.8°.

Example 14 Characterisation of Salt by IR Spectroscopy

The IT-IR spectrum of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneglycolate prepared in accordance with Example 12 is measured using thetransmission KBr technique (in a KBr-disc with ca. 1.1/302mg) and aBRUKER OPTICS IFS-55™ Fourier Transform Infrared (FTIR) spectrometer.The IT-IR spectrum thus determined is shown in FIG. 2. Major IR bandsare recorded Main IR bands: 3169; 2965; 1657; 1599; 1552; 1491;1431;1390; 1298; 1226;1088; 1061; 875; 829; 742; 699; 543 cm⁻¹.

Example 15 Preparation of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneacetate

2.168 g(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onebase (5.523 mmoles) and 1.17 g acetic acid (19.48 mmoles) are dissolvedin 60 ml isopropanol at 80° C. The clear solution is allowed to coolslowly. Crystallization takes place spontaneously at 35° C. Thesuspension is stirred for 17 hours at room temperature and thenfiltered. The filter cake is washed with 10 ml isopropanol and dried at60° C./ca 10 mbar for 20 hours.

Yield: 2.123 g white crystals (84.9%)

Elemental analysis:

Calc.: 69.01% C; 7.13% H; 6.19% N; 17.68% O

Found: 68.92% C; 6.98% H; 6.12% N; 17.67% O

Example 16 Characterisation of Salt by X-ray Powder Diffraction

The X-ray diffraction pattern of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneacetate prepared in accordance with Example 15 is measured using aSCINTAG™ X-ray diffractometer with a CuK alpha radiation source. TheX-ray diffraction pattern thus determined is shown in FIG. 3 andrepresented in Table II below by the reflection lines and intensities ofthe most important lines.

TABLE II X-ray diffraction lines and intensities for the acetate saltRelative 2θ (°) d-spacings (Å) intensity 4.3 20.36 S 8.4 10.48 M 11.47.78 M 15.1 5.88 S 17.0 5.21 L 18.6 4.76 L 19.1 4.64 L 19.7 4.49 L 20.54.32 L 22.9 3.87 L 23.3 3.82 L 23.5 3.78 M 24.6 3.61 L 25.6 3.48 L 28.93.09 L 30.5 2.93 L

The XRPD pattern shows a strong diffraction peak at 4.3°.

Example 17 Characterisation of Salt by IR Spectroscopy

The IT-IR spectrum of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneacetate prepared in accordance with Example 15 is measured using thetransmission KBr technique (in a KBr-disc with ca. 1.1/300 mg) and aBRUKER OPTICS IFS-55™ Fourier Transform Infrared (FTIR) spectrometer.The IT-IR spectrum thus determined is shown in FIG. 4. Major IR bandsare recorded Main IR bands: 3409; 2964; 1663; 1613; 1546; 1491;1417;1396; 1293; 1231; 1165; 1029; 873; 838; 816; 663 cm⁻¹.

Example 18 Preparation of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onexinafoate

5.0 g(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onebase (12.738 mmoles) and 2.40 g 1-hydroxy-2-naphthoic acid (12.626mmoles) are dissolved in 60 ml n-butanol at 100° C. The solution isallowed to cool. Some seeds are added at 25° C. and crystallizationtakes place slowly. The suspension is stirred for 17 hours at roomtemperature and then filtered. The crystals are washed with 10 mln-butanol and dried at 70° C. and ca. 10 mbar for 20 hours. Yield: 5.57g beige powder (76%).

Elemental analysis:

Calc.: 72.40% C; 6.25% H; 4.82% N; 16.53% O

Found: 72.16% C; 6.18% H; 4.81% N; 16.47% O

Example 19 Characterisation of Salt by X-ray Powder Diffraction

The X-ray diffraction pattern of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onexinafoate prepared in accordance with Example 18 is measured using aSCINTAG™ X-ray diffractometer with a CuK alpha radiation source. TheX-ray diffraction pattern thus determined is shown in FIG. 5 andrepresented in Table III below by the reflection lines and intensitiesof the most important lines.

TABLE III X-ray diffraction lines and intensities for the xinafoate saltRelative 2θ (°) d-spacings (Å) intensity 4.1 21.72 S 10.0 8.87 M 12.27.25 M 12.9 6.85 M 18.2 4.86 L 20.9 4.25 L 25.9 3.43 L

The XRPD pattern shows a strong diffraction peak at 4.1°.

Example 20 Characterisation of Salt by IR Spectroscopy

The IT-IR spectrum of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onexinafoate prepared in accordance with Example 18 is measured using thetransmission KBr technique (in a KBr-disc with ca. 1.2/305 mg) and aBRUKER OPTICS IFS-55™ Fourier Transform Infrared (FTIR) spectrometer.The IT-IR spectrum thus determined is shown in FIG. 6. Main IR bands:2964; 1661; 1611; 1582; 1467;1435; 1404; 1303; 1255; 1172; 1079; 1054;829; 795; 773; 624; 537 cm⁻¹.

Example 21 Preparation of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen malonate

A suspension of 2.172 g(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onebase (5.533 mmoles) and 0.576 g malonic acid (5.533 mmoles) in 25 mln-butanol is heated to 80° C. Initially an oil formed during heating,which crystallizes on prolonged heating. The mixture is stirred at 80°C. for 15 minutes and then allowed to cool to room temperature. Thesuspension is stirred for 18 hours at room temperature. After filtrationthe crystals are washed with 5 ml n-butanol and 10 ml acetone. Theproduct is dried at 70° C. and 70° C. for 20 hours. Yield: 2.62 g whitepowder (95.28%)

Elemental analysis:

Calc.: 65.31% C; 6.50% H; 5.64% N; 22.55% O

Found: 65.21% C; 6.50% H; 5.75% N; 22.49% O

Example 22 Characterisation of Salt by X-ray Powder Diffraction

The X-ray diffraction pattern of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen malonate prepared in accordance with Example 21 is measuredusing a SCINTAG™ X-ray diffractometer with a CuK alpha radiation source.The X-ray diffraction pattern thus determined is shown in FIG. 7 andrepresented in Table IV below by the reflection lines and intensities ofthe most important lines.

TABLE IV X-ray diffraction lines and intensities for the hydrogenmalonate salt Relative 2θ (°) d-spacings (Å) intensity 5.2 17.03 S 10.48.53 L 13.3 6.67 S 14.2 6.21 M 15.7 5.64 M 16.0 5.54 L 16.7 5.31 L 19.34.60 M 20.3 4.36 L 21.0 4.23 M 21.4 4.15 L 21.7 4.09 L 22.6 3.92 M 25.43.50 L 25.8 3.45 L 26.3 3.38 M 26.7 3.33 L 28.7 3.11 L 29.8 2.99 L 32.42.76 L

The XRPD pattern shows a strong diffraction peak at 13.3°.

Example 23 Characterisation of Salt by IR Spectroscopy

The IT-IR spectrum of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)4-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen malonate prepared in accordance with Example 21 is measuredusing the transmission KBr technique (in a KBr-disc with ca. 1.3/303 mg)and a BRUKER OPTICS IFS-55™ Fourier Transform Infrared (FTIR)spectrometer. The IT-IR spectrum thus determined is shown in FIG. 8.Main IR bands: 3306; 2964; 1644; 1604; 1563; 1484; 1426; 1387; 1317;1272; 1154; 1051; 826; 758; 689 cm⁻¹.

1. A compound of formula I

in salt or solvate form, where W is a group of formula

R^(x) and R^(y) are both —CH₂— or —(CH₂)₂—; R¹ is hydrogen, hydroxy, orC₁-C₁₀-alkoxy; R² and R³ are each independently hydrogen orC₁-C₁₀-alkyl; R⁴, R⁵, R⁶ and R⁷ are each independently hydrogen,halogen, cyano, hydroxy, C₁-C₁₀-alkoxy, C₆-C₁₀-aryl, C₁-C₁₀-alkyl,C₁-C₁₀-alkyl substituted by one or more halogen atoms or one or morehydroxy or C₁-C₁₀-alkoxy groups, C₁-C₁₀-alkyl interrupted by one or morehetero atoms, C₂-C₁₀-alkenyl, trialkylsilyl, carboxy,C₁-C₁₀-alkoxycarbonyl, or —CONR¹¹R¹² where R¹¹ and R¹² are eachindependently hydrogen or C₁-C₁₀-alkyl, or R⁴ and R⁵, R⁵ and R⁶, or R⁶and R⁷ together with the carbon atoms to which they are attached denotea 5-, 6- or 7-membered carbocyclic ring or a 4- to 10-memberedheterocyclic ring; R⁸, R⁹ and R¹⁰ are each independently hydrogen orC₁-C₄-alkyl; and A is selected from the group consisting of hydrogensuccinate, fumarate, hippurate, mesylate, hydrogen sulphate, hydrogentartrate, hydrogen chloride, hydrogen bromide, formate, esylate,tosylate, glycolate, acetate, xinafoate and hydrogen malonate.
 2. Acompound according to claim 1, wherein R⁸, R⁹ and R¹⁰ are each H, R¹ isOH, R² and R³ are each H and (i) R^(x) and R^(y) are both —CH₂—, and R⁴and R⁷ are each CH₃O— and R⁵ and R⁶ are each H; (ii) R^(x) and R^(y) areboth —CH₂—, and R⁴ and R⁷ are each H and R⁵ and R⁶ are each CH₃CH₂—;(iii) R^(x) and R^(y) are both —CH₂—, and R⁴ and R⁷ are each H and R⁵and R⁶ are each CH₃—; (iv) R^(x) and R^(y) are both —CH₂—, and R⁴ and R⁷are each CH₃CH₂— and R⁵ and R⁶ are each H; (v) R^(x) and R^(y) are both—CH₂—, and R⁴ and R⁷ are each H and R⁵ and R⁶ together denote —(CH₂)₄—;(vi) R^(x) and R^(y) are both —CH₂-, and R⁴ and R⁷ are each H and R⁵ andR⁶ together denote —O(CH₂)₂O —; (vii) R^(x) and R^(y) are both —CH₂—,and R⁴ and R⁷ are each H and R⁵ and R⁶ are each CH₃(CH₂)₃—; (viii) R^(x)and R^(y) are both —CH₂—, and R⁴ and R⁷ are each H and R⁵ and R⁶ areeach CH₃(CH₂)₂—; (ix) R^(x) and R^(y) are both —(CH₂)₂—, R⁴, R⁵, R⁶ andR⁷ are each H; or (x) R^(x) and R^(y) are both —CH₂—, and R⁴ and R⁷ areeach H and R⁵ and R⁶ are each CH₃OCH₂—.
 3. A compound according to claim1 or 2, wherein A is selected from the group consisting of glycolate,acetate, xinafoate and hydrogen malonate.
 4. A compound according toclaim 1 or 2 that is selected from the group consisting of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen succinate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onefumarate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehippurate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onemesylate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen sulfate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen tartrate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen chloride,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen bromide,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneformate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneesylate, and(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onetosylate.
 5. A compound according to any one of claims 1 to 3 that isselected from the group consisting of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneglycolate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneacetate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onexinafoate, and(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen malonate.
 6. A pharmaceutical composition comprising, as activeingredient, an effective amount of a compound of claim 1, optionallytogether with a pharmaceutically acceptable carrier.
 7. A pharmaceuticalcomposition according to claim 6, wherein the active ingredient isselected from the group consisting of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen succinate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onefumarate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehippurate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onemesylate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen sulfate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen tartrate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen chloride,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen bromide,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneformate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneesylate and(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onetosylate.
 8. A pharmaceutical composition according to claim 6, whereinthe active ingredient is selected from the group consisting of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneglycolate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneacetate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onexinafoate, and(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen malonate.
 9. A pharmaceutical composition according to claim 6,which is in inhalable form.
 10. A pharmaceutical composition accordingto claim 6, that further comprises as active ingredient one, two, threeor more anti-inflammatory, bronchodilatory, antihistaminic/anti-allergicor anti-tussive drug substances.
 11. A pharmaceutical compositionaccording to claim 10, that further comprises as active ingredient oneor both of mometasone and glycopyrrolate.
 12. The use of a compound offormula I for the preparation of a medicament for the treatment of aninflammatory or obstructive airways disease.
 13. The use of a compoundof formula I for the preparation of a medicament for the treatment ofasthma or chronic obstructive pulmonary disease.
 14. The use accordingto claim 12 or 13 wherein the compound of formula I is selected from thegroup consisting of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen succinate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onefumarate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehippurate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onemesylate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen sulfate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen tartrate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen chloride,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen bromide,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneformate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneesylate, or(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onetosylate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneglycolate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-oneacetate,(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onexinafoate, and(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onehydrogen malonate.
 15. A process for preparing a compound of claim 1comprising: (i) for the preparation of compounds of formula I where A ishydrogen succinate, reacting the free base with succinic acid; (ii) forthe preparation of compounds of formula I where A is fumarate, reactingthe free base with fumaric acid; (iii) for the preparation of compoundsof formula I where A is hippurate, reacting the free base with hippuricacid; (iv) for the preparation of compounds of formula I where A ismesylate, reacting the free base with methanesulfonic acid; (v) for thepreparation of compounds of formula I where A is hydrogen sulphate,reacting the free base with sulfuric acid; (vi) for the preparation ofcompounds of formula I where A is hydrogen tartrate, reacting the freebase with (+)-L-tartaric; (vii) for the preparation of compounds offormula I where A is hydrogen chloride, reacting the free base withhydrochloric acid; (viii) for the preparation of compounds of formula Iwhere A is hydrogen bromide, reacting the free base with hydrobromicacid; (ix) for the preparation of compounds of formula I where A isformate, reacting the free base with formic acid; (x) for thepreparation of compounds of formula I where A is esylate, reacting thefree base with ethansulfonic acid; (xi) for the preparation of compoundsof formula I where A is tosylate, reacting the free base withp-toluenesulfonic acid; (xii) for the preparation of compounds offormula I where A is glycolate, reacting the free base with glycolicacid; (xiii) for the preparation of compounds of formula I where A isacetate, reacting the free base with acetic acid; (xiv) for thepreparation of compounds of formula I where A is xinafoate, reacting thefree base with 1-hydroxy-2-naphthoic acid; or (xv) for the preparationof compounds of formula I where A is, hydrogen malonate, reacting thefree base with malonic acid.